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【结 构 式】 
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【分子编号】44817 【品名】(3S)-2-[(2R)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-7-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C27H27FN2O4 【 分 子 量 】462.5208632 【元素组成】C 70.12% H 5.88% F 4.11% N 6.06% O 13.84% |
合成路线1
该中间体在本合成路线中的序号：(VIIIa)(S)-7-Hydroxy-1,2,3,4-tetrahydroqinoline-3-carboxylic acid (I) is N-protected by means of di-tert-butyldicarbonate (Boc2O) and Na2CO3 in H2O/dioxane and then converted into methyl ester derivative (II) by treatment with trimethylsilyl diazomethane (TMSCNH2). Reaction of (II) with triflic anhydride (Tf2O) and Et3N in CH2Cl2 yields triflate (III), which is then coupled to boronic acid (IV) by Suzuki cross-coupling reaction in the presence of Pd(PPh3)4 and Na2CO3 in toluene/EtOH, providing derivative (V). Boc removal in (V) by treatment with HCl/HOAc followed by coupling with N-Boc-2,6-dimethyl-D/L-tyrosine (VIa-b) by means of EDC, HOBt, DIEA and DMAP in DMF furnishes protected compound (VIIa-b). Compound (VIIa-b) is hydrolyzed with LiOH and N-deprotected by means of HCl/HOAc to afford a mixture of diastereomers (VIIIa-b) from which the target compound is separated by reverse-phase HPLC.
| 【1】 Brown, W.; Mischki, T.; Butterworth, J.; Schmidt, R.; McGlory, A.; Payza, K.; St-Onge, S.; Labarre, M.; Pagé, D.; Novel Dmt-Tic dipeptide analogues as selective delta-opioid receptor antagonists. Bioorg Med Chem Lett 2000, 10, 2, 167. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VIIa) | 44185 | 5,6-diamino-3-methyl-1-phenyl-2,4(1H,3H)-pyrimidinedione | C11H12N4O2 | 详情 | 详情 | |
| (VIa) | 44813 | (2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-2,6-dimethylphenyl)propionic acid | C16H23NO5 | 详情 | 详情 | |
| (VIb) | 44814 | (2S)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-2,6-dimethylphenyl)propionic acid | C16H23NO5 | 详情 | 详情 | |
| (VIIb) | 44816 | methyl (3S)-2-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-7-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylate | C33H37FN2O6 | 详情 | 详情 | |
| (VIIIa) | 44817 | (3S)-2-[(2R)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-7-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid | C27H27FN2O4 | 详情 | 详情 | |
| (VIIIb) | 44818 | (3S)-2-[(2S)-2-amino-3-(4-hydroxy-2,6-dimethylphenyl)propanoyl]-7-(4-fluorophenyl)-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid | C27H27FN2O4 | 详情 | 详情 | |
| (I) | 44809 | (3S)-7-hydroxy-1,2,3,4-tetrahydro-3-isoquinolinecarboxylic acid | 128502-56-7 | C10H11NO3 | 详情 | 详情 |
| (II) | 44810 | 2-(tert-butyl) 3-methyl (3S)-7-hydroxy-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylate | C16H21NO5 | 详情 | 详情 | |
| (III) | 44811 | 2-(tert-butyl) 3-methyl (3S)-7-[[(trifluoromethyl)sulfonyl]oxy]-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylate | C17H20F3NO7S | 详情 | 详情 | |
| (IV) | 38403 | 4-fluorophenylboronic acid | 1765-93-1 | C6H6BFO2 | 详情 | 详情 |
| (V) | 44812 | 2-(tert-butyl) 3-methyl (3S)-7-(4-fluorophenyl)-3,4-dihydro-2,3(1H)-isoquinolinedicarboxylate | C22H24FNO4 | 详情 | 详情 |